Trans-octahydro - 4a - lower alkyl-5-(t-butoxy or benzyloxy) - 2 -oxo-1-(4-substituted - 3 - oxobutyl)-1-naphthaldehydes

ABSTRACT

THIS DISCLOSURE DESCRIBES COMPOUNDS OF THE CLASS OF TRANS-1,2,4A,5,6,7,8,8A-OCTAHYDRO-4A-LOWER ALKYL-5-(T - BUTOXY OR BENZYLOXY)-2-OXO-1-(4-SUBSTITUTED3-OXOBUTYL)-1NAPHTHALDEHYDES USEFUL AS INTERMEDIATES IN THE SYNTHESIS OF BIOLOGICALLY ACTIVE STEROID MOIETIES.

3,660,490 Patented May 2, 1972 UnitedStates Patent 3,660,490 TRANS-OCTAHYDRO '...4a LOWER ALKYL-S- (t-BUTOXY OR BENZYLOXY) .2 X0- 1-(4-.: SUBSTITUTED 3 ()XOBUTYL)-l-NAPH'IH ALDEHYDES y p 7 Marinus Los, Trenton, N.J., assignorto American Cyanamid Company, Stamford, Conn; No Drawing. Original application Ju'ne'4, "1964, Ser. No. 372,690, now' Patent No. 3,446,849. Divided and this application Jan. 6, 1969,Ser. No. 789,366 Int. Cl. C07c 49/54, 45/00, 47/44.; L US. Cl. 260-586 R 2 Claims ABSTRACT on DISCLOSURE This disclosure describes compounds of the class of trans-1,2,4a,5,6,7,8,8a-octahydro-4a-lower alkyl-S-(t butoxy or benzyloxy) -2-oxo-1-(4-substituted-3-oxobutyl)-lnaphthaldehydes useful as intermediates in the synthes s of biologically active steroid moieties.

DETAILED DESCRIPTION OF THE INVENTION. This application is a division of my copending application Ser. No. 372,690, filed June 4, 1964 now U.S. Pat.- No. 3,446,849.

BRIEF SUMMARY OF THE. INVENTION This invention relates to new organic compounds and,- more particularly, it relates to novel compounds useful in the synthesis of a biologically active steroid moiety.

The compounds of the present invention-may be-jillustrated by the following-formula: l r

wherein R is selected from the group consisting of benzyl and tertiary butyl, R is lower alkyl and X isselected from the group consisting of lower alkyl 0 CH0; lower-alkyl-occn O.

lower alkylwgcli cli 0 (Q are DETAILED DESCRIPTION QETH'E INVENTION The compounds of the present invention are usually,

viscous oilsor crystalline solids; w I 0 Among the compounds within the scopeoflth presentv invention are the following: 7 I I methyl trans-l-formyl-l,2,4a',5,6,7,8,8a-octahydro*4a- L methyl-S-t-butoxy-6,2-dioxo-l-naphthaleneheptanoateg K methyl trans-l-formyl-l,2,4a,5,6,7,8,8a-octahydro=4a ethyl-5-t-butoxy-6,2-dioxo-l-naphthaleneheptanoate; methyl trans-l-formyl-1,2,4a,5,6,7,8,8a-octahydro-4amethyl-5-benzyloxy- 6, 2' dioxo-l-naphthaleneheptanoate; 6

methyl trans-l-formyl-1,2,4a,5;6,7,8,8a-octahydro-4aethyLS-benzyloxyifi,Z-dihxoel-naphthaleneheptanoate;

trans-1,2,4a,5,6,7,8,8a-octahydro-4a metliyl-5-t-butoxy-2- 0x0- 1- 3-oxobutyl) l-naphthaldehyde;

trans-1,2,4a,5,6,7,8,8a-octahydro-4a-ethyl-5-t-butoxy-2- oxo- 1- (3-oxobutyl) l-naphthaldehyde;

trans-1,2,4a;5,6,7,8,8a-octahydro-4a-methyl-S-benzyloxy- 2-oxo-1-(3-oxobutyl)-1-naphthaldehyde; trans-1, 2,4a,5, 6,7,8,8a-octahydro-4a-ethyl-S-benzyloxy-Z- oxol-(fi-oxobutyl)-l-naphtha1dehyde; I trans-1,2,4a,5,6,7,8,Sa-octahydro-4a-methyl-5-benzyloxy- 2-oxo-1-(3 oxopentyl)-l-naphthaldehyde; trans-l,2,4a,5,6,7,8,8a-octahydno-4a-methyl-5-t-butoxy-2- oxo-1-(3-oxopentyl)-1-naphthaldehyde; transgl,2,4a,5 ,6,7,8,8a-octahydro-4a-ethyl-S-benzyloxy- Z'oxo-1-(3-oxopentyl)-l-naphthaldehyde; trans-1,2,4a,5,6,7,8,8a-octahydro-4a-ethyl-5-t-butoxy-2- oxo-1-(3-oxopentyl)-1-naphthaldehyde and the like.

-The present compounds are prepared by using starting materials such as, for example, 2-lower alkylcyclohexane-' 1,3-rlione (compound I) in the flowsheet hereinafter which is reacted with methylvinyl ketone in the presence of an alkali metal hydroxide in alcohol and adding to this mixture benzene and pyrrolidine to form a 1,6-dioxo-A -9- lower alkyloctalin (II). This material (II) is separated from the mixture and then treated with sodium borohytitative. yield. The crude enol ether (V) l-acyloxy-G-lower pound. (VII) when refluxed with ethylene glycol and palkoxyr9-lower alkyl-A -hexahydronaphthalene may thefnhe hydrogenated catalytically to the new compound I-acyloxy-6lower' alkox y-9-lower alkyl-trans-A -octalin (VI), which without purification, is warmed with aqueous acetic acid to give .1-acyloxy 6-oxo-9-lower alkyltransfd ecalin (VII). The subject matter shown hereinafter in the flowsheet as compounds IV through VII is described and claimed in my copending application Ser. No.

360,404, filed Apr. 16, 1964, now US. Pat. No.- 3,331,856 ,The l acyloxy-6-oxo-9-lowe r alkyl-trans-decalin comtoluenesulphonic acid in a solvent, yields 1-acyloxy-6,6-

ethylenedioxy-9-lower alkyI-trans-decalin (X-H) which in; turn is readily converted to 6,6-ethylenedioxy-l-hydroxy-.

9-lower alkyl-trans-decalin (XIII) by refluxing with any alcoholic solution of an alkali metal hydroxide, preferably ethanolic potassium hydroxide.

When a l-hydroxy-6,6-ethylenedioxy-9-lower alkyltrans-decalin (compound Xlllfisheated with benzyl chloride and sodium hydride, an excellent yield of the l-benzyloxy (compound XIV) derivative, is formed. As an example, 1-hydroxy-6, 6ethylenedioxy-Q-methyl-trans-decalin with benzyl chloride and sodium hydride yields 1 benzyloxy-6,6eethylenedioxy-9-methyl-trans-decalin.

Hydrolysis of the 6,6-ethylenedioxy 'ketal function (compounds XIV) is readily accomplished by warming the ketal with'aqueous acetic acid. Mineral acids in an organic solvent miscible'with water can also-be'used. As a specific example, when 1-benzyloxy-6,6-ethylenedioxy-9-methyl 3 trans decalin (compound 'XIV) is warmed with 30%-'- aqueous acetic acid, the product obtained in excellent yield is 11benzyloxy-6-oxo-9-methyl trans-decalin (compound 7 When the compounds, represented by Formula XV, in an inertsolvent, preferably'chloroform, are treated with bromine in the same solvent, an excellent yield of the corresponding bromo derivative (XVI) is formed. As a specific example, when 1-benzyloxy-6-oxo-9-methyl-transdecalin is treated with bromine in chloroform, a good yield of 1-benzyloxy-7-bromo-6-oxo-9-methyl-trans-decalin is formed. The bromo compounds (XVI) are dehydrobrominated in excellent yields by heating under reflux a solution of (XVI) in dry dimethylformamide containing anhydrous lithium halide, preferably lithium chloride, and anhydrous lithium carbonate in an inert atmosphere. Such reaction yields, for example, 1-benzyloxy-6-oxo-9-lower alkyl-A' -trans-octalin (XVII). For example, when l-benzyloxyJ-bromo-6-oxo-9-methyl-trans-decalin is dehydrobrominated in dimethylformamide in the presence of lithium carbonate, an excellent yield of 1-benzyloxy-6- oxo-9-methyl-A -trans-octalin is formed.

By the different route, the l-acyloxy-6-oxo-9-lower alkyl-trans-decalins (VII) of the general formula:

mom 2 wherein R is lower alkyl and R is selected from the group consisting of hydrogen, lower alkyl, phenyl and substituted phenyl radicals (i.e. tolyl, halophenyl, and the like), is dissolved in an inert solvent, preferably chloroform, bromine, preferably dissolved in the same solvent, is then admixed with this solution to yield the corresponding bromo derivative, for example, l-lower alkanoyloxy- 7-bromo-6-oxo-9-lower alkyl-trans-decalin (VIII).

Dehydrobromination of this product is carried out by heating a solution of product (VIII) in dimethylformamide with a lithium halide, preferably lithium chloride,

and preferably in the presence of lithium carbonate, thereby yielding the corresponding A derivative (IX). Hydrolysis of this latter product (IX) is carried out with a weak base, preferably potassium bicarbonate, a mixture of water and an inert organic solvent, preferably ethanol, miscible with water to yield the corresponding l-hydroxy derivative (X) of the flowsheet hereinafter.

The 1-t-butoxy-6-oxo-9-lower (XI) is formed by reaction of the above-identified l-hydroxy derivative (X) with isobut ylene in an inert solvent,

preferably methylene chloride, in the presence of a strong acid catalyst, preferably phosphoric acid-boron trifiuoride.

The compounds (VHI through XI) in the flowsheet hereinafter are described and claimed in my copending application Ser. No. 372,688, filed June 4, 1964, now US. Pat. No. 3,321,511, and compounds (XIV through XVII) in my copending application Ser. No. 372,716, filed June 4, 1964, now US. Pat. No. 3,321,488.

The compound alkyl-A trans-octalin n. v OR' new wherein R is selected from the group consisting of benzyl and tertiary butyl and R is lower alkyl.

When compound (XIX) is reacted with c p-unsaturated ketones, preferably vinyl ketones, in the presence of an alkali metal alkoxide, preferably potassium-t-butoxide, in an inert solvent, preferably t-butanol, under an inert atmosphere, there is formed a compound of the Formula XX in good yield which may be illustrated as follows:

R" o i H 0 CH0 wherein R is lower alkyl, R is selected from the group consisting of t-butyl and benzyl and R" is selected from the group consisting of hydrogen, lower alkyl, lower alkyl acetate and lower alkyl propionate. As specific examples, when the compound trans-l,2,4a,5,6,7,8,8a-octahydro-4amethyl-5-t-butoxy-2-oxo-l-naphthaldehyde is treated with an aqueous solution of an alkali metal hydroxide, preferably sodium hydroxide, in' an inert atmosphere. As a specific example, methyl trans-l-formyl-1,2,4a,5,6,7,8,-8aoctahydro-4a-methyl-S-benzyloxy-fi-Z-dioxo-1 naphthaleneheptanoate, represented generically by Formula XX,

, on treatment with sodium hydroxide in aqueous dioxane yields dl-2,3,'4,4a;S,4bu,5,-6,7,8,8a-decahydro-8ap methyl- SB-benzyloxy-2-oxo-phenanthrene-l-propionic acid, represented generically by (XXI) as follows:

ita

wherein R is lower alkyl, R is selected from the group consisting of t-butyl and benzyl and R' is selected from the group consisting of hydrogen, lower alkyl, acetic acid and propionic acid. Where the above-mentioned hexenoate is used in the reaction, R for compounds represented by (XXI) is acetic acid.

The compounds (XXII) of the flowsheet may be illustrated by the formula:

wherein R is lower alkyl, R is selected from the group consisting of t-butyl and benzyl and R' is selected from the group consisting of hydrogen, lower alkyl, aceticacid and propionic acid.

The reduction of compounds (XXI to XXII) is carried out with hydrogen and a hydrogenation catalyst, preferably 'palladium on strontium carbonate'Two solvent systems are employed in the reduction. WhenXXI (R"' is CH CH COOI-I or '--CI-I COH) is the substrate, water containing one equivalent of an-alkali metal hydroxide, preferably sodium hydroxide, is used. When XXI (R is or lower alkyl) is the substrate, an inert solvent, preferably benzene, is used. As a specifie'example, dl-8fl-benzylwry-2,3,4,4afl,4ba,5,6,7,8,8a-decahydroe8ap methyl 2- oxo-phenanthrene-l-propionic acid (XXI, R is CH R is CH C H R" is CH CH COOH) on reduction with hydrogen in water containing one equivalent of sodium hydrox-ide in the presence of palladium on strontium carbonate give dl Sfi-benzyloxy-Z,3,4,4ap,4ba,5,6,7,8,8a;9,l0- dodecahydro-8ae-methyl-Z-oxo-phenanthren 1 propionic acid (XXII, R -is CH R is 'CH C H R'" is CH CH COOH) Where; the corresponding aceticgacid analog of (XXI, R' is LCH COOH) is reduced" with hydrogen in water, the corresponding acetic acid compound (XXILR? is CH COOH) is found. i I i 'Although the examples above are specific for R as rnet-hyl, the processes are equally applicable when R is lower 'alkyl and the invention includes the compounds in which R is a lower alkyl radical. i

tate gives in good yield dl-l7a,p-benzyloxy-5-hydroxy-3,5- seco-4-nor-5(l0),9(11) D homoestradien-3-oic acid, 3,5-lactone (XXIII, in which R is CH Treatment of (XXII, where R is CH COOH), yields dl-13 lower alkyl-l7a-benzyloxy-l,4 bisnor-3,5 seco 5 hydroxy- D-homo-g'ona-S 10) ,9( 1 1 -dien-3-oic acid, 3,5-lactone.

Reduction of compounds (XXIII) with hydrogen and a hydrogenation catalyst, preferably palladium or strontium carbonate in an inert solvent, such as benzene, gives, in excellent yield (compounds XXIV). As for example, dl-l7a,)8-benzyloxy 5 hydroxy 3,5 seco 4 nor-5 (l0),9(1l)-D-hornoestradien 3 oic acid, 3,5 lactone (XXIII, wherein R is CH on reduction gives dl-17a,fibenzyloxy 5 hydroxy 3,5-seco-4-nor-5(10)-D-homoestr'en-3-oic acid, 3,5-lact0ne (XXIV, wherein R is CH Finally, when compounds (XXIV) are treated with a methyl magnesium halide, such as the bromide, and the crude product allowed to stand in a mixture of acetic and hydrochloric acids, compounds (XXV) are formed in good yield. For example, dl-l7a,;9-benzyloxy-5-hydroxy- 3,5 seco- 4-nor 5(l0)-D-homoestren 3-oic acid 3,5- lactone (XXIV, wherein R is CH gives on treatment with methyl magnesium bromide followed by acid a good yield of dl-l9-nor-D-homotestosterone, benzylether (compound XXV, wherein R is CH3).

This compound (XXV) can be transformed into the known biologically active compound dl-19-nor-D-homotestosterone by removing the benzyl blocking group. This can be removed by reduction with lithium in liquid ammonia after protecting the keto group as the ethylenedioxy ketal,'and subsequent acid hydrolysis of the ketal.

FLOWSHEE'I' OCOR' In the above flowsheet R, R R" and R' are as hereinbefore defined an R is lower alkyl.

When the compounds (XXIIwherein I? is t-butyl) are treated with acetic anhydride-sodium acetate, good yields of compounds (XXIII or XXIIIA) are pro duced. As a specific example, the treatment of dl-Sflbenzyloxy 2,3,4,4a 3,4ba,5,6,7,8,8a,9,10 dodecahydro- 8a 3 methyl 2'- oxo-phenanthrene-l propionic acid (in which R is CH with acetic anhydride. and sodium aceo t u I OH R R2 1 2 2 Ci we aridm oil 0 0 I 0 R0 I: Y 1 III 1v v r OCOR' OCOR' a occa- 4,- .r I O vrn I v11: 9

i H R R201! R ocon' Of) 03115 When the starting material is dl-l7ap-benzyloxy-5-hydroxy 3,5 seco 4 5(10) D homogonene-3-oic acid, 3,5-lactone (compounds XXIV, wherein R is C2 15), the final product will be d1 13-ethyl-l9 nor-D-homo-4-gonenel'lafl-ol (compounds XXV, wherein R is ethyl and R is When d1 .17afi-t-butoxy-5-hydroxy 3,5 seco-4-nor- '5(lO)-D-homoestren 3 oic acid, 3,5-lact0ne (compounds XXIV, wherein R is CH and R is t-butyl) is treated withmethyl magnesium bromide followed by acid, the product is directly dl 19 nor-D-homotestosterone, the t-butyl blocking group having been removed during the acid treatment.

Similarly, when the starting material is dl .17yafl-toctalin, l ml.acetic anhydrideand 2 ml. pyridine are butoxy 13 ethyl hydroxy 3,5 seco-4-nor-5(10); heated on a steam bath for 1.5 hours. Thevs olution is D-homogonene 3 oic acid, 3,5 lactone (compounds then poured into -3Q01ml.,ice-water with stirring. After XXIV, wherein R is C H and R is t-butyl) and it iscarstirring for l hour, the aqueous mixture is extractedlwith ried through the identical reaction sequence, the product ether and the ether-washed with water, saturated sodium is dl 13 ethyl-19-nor-D-homo-4-gonene-l7a13 ol (combicarbonate solution, dried and evaporated. The l-acetoxypounds XXV, wherein R is ethyl and R is H)... 6:0x0- A Q -9eethyloctalin is obtained as a colorless oil,

The following examples describe the use of-starting ma; weighing ,4.2 grand is used without further purification. terials, such as 2-lower alkylcyclohexane-1,3-diones to pre; The above reaction, when condensed with the appro pare the present compounds and subsequently converting priatel-hydroxy-6-oxo-A Q .-9+lower alkyloctalin in presthe present compounds to the biologically active d1- l 9-nor-, ence. of pyridine and the appropriate acyl anhydride or D-homotcstosterone. aroyl',halide:yields the corresponding, l-acyloxy-6 oxo- EXAMPLEi v v A ,9 -9-lowerl alkyloctalin or.1raroyloxy-6-oxo-A -9- loweralkyloctalin, for example, 1-propionyloxy-6-oxo- Preparation of 1,6-dioxo-A- -9-ethyloctalin (ll)' 1' A -9-propyloctalinior 1-benzyloxy-6-oXo-A 9-meth- EXAMPLE 4 emf 62 m1. of methylvinyl ketone, 0.25 g. potassium'hy- I I 1 droxide and 250 ml. absolute methanol are heated with 3 I I I Preparation of I acetoxy-6 ethoxy-9-methyl :1 stirring under reflux for 4 hours. Methanol and excess 20. A4(1o)'ihexahydronapmhalene (v) methylvinyl ketone are then removed by distillation at at- I mospheric pressure. Benzene is added to the residue and Toa solution of 44.4 grams (0.2 mole) of l-acetoxy; the distillation continued until the temperature of the 6-oxo-9-'methyl-A t l octalin irr44 ml. ethyl orthoformate, vapours is 80 C. indicating complete removal 'of meth- 4 ml. absoluteethanol and 200ml. benzene is added 4 ml.

anol and water. Benzene is added to bring the volume of of absolute ethanol saturated with hydrogen chloride and the solution up to the original volume. The solution iS the mixture is heated under refluxing conditions for 2 cooled in an ice bath and 3 ml. pyrrolidine is added. The hours. The mixture is cooled, diluted with an equal. volsolution is heated under reflux under a Dean-Stark water time of ether and poured into, 300 ml. of 5% sodium separator for 1 hour when no more water is azeotropicalhydroxide solution. After shaking thoroughly, the aqueous ly distilling. The solution is cooled in ice, dilutedv with phase is discarded. The organic phase is-washed'with ether and washed with 100 ml. water containing 15 ml. 3 water, saturated brine, dried and the solvent evaporated, of a 10% hydrochloric acid solution, followed by 100 ml. The residue, a yellow mobile oil, which can be crystalwater. The aqueous phases are combined and washed with :Lliziedtoa colorless hydroscopic solid is essentially pure 50 m1. ether. The combined organic phases are washed 1-actoxy 6-ethoxy-9-methyl-A hexahydronaphthawith three 100 ml. portions of water, saturated brine, dried 2" lane as determined spectroscopically. This material is used and evaporated. The residue is distilled. The main fracdirectlyjor the preparation of l-acetoxy-6=ethoxy 9-methtion boils at 130135 C. at 0.06 mrnfThe distillate yI-trans A -octaIin (VI)."

is crystallized from ether-hexane to yield 46.7 g..of 1,6- i w i dioxo-A -9-ethyloctalin. The analytical sample obtained EXAMPLE 5 by recrystallizations from ether-hexane has melting point Preparation of 1-acetoxy-6-ethoXy-9-ethyl- 67.5-68.5 C. W M A Q -hexahydronaphthalene (V) The q Y alkylwalms are .P? z I "The crude'1 acetoxy-fiaoxon l -9-ethyloctalin (4.2 g.) by supsmutmg the appm-Pnate zt'l-ower alkylcyclqhxanek (Example 3 5.6 mLethylforthoforrnate, 1 ml. absolute 1341mm 9 the 2 g i gzt 1:133 3P gf et'hanol, 1 ml. absolute ethanolsaturated with hydrogen above .reactlon' exam? a e w i chloride and 100 ml} benzene are heated under reflux for yloctahn and X- f Q.j are wa 2 hours -The;solution is cooled, wdiluted with ether, and Prepared by P ashe'd with 1 0 m1. of 5% sodium hydroxide followed by EXAMPLE 2 I washings with water "and saturated brine. The organic 5(10) 1 phase-is dried and evaporated to yield l-acetoxy- 6-ethoxy- Preparanon of 1 PY f f 9-ethyl-A -lrexahydronaphthalene as a pale yellow oil To an ice-cold stirred solution of 9.6 g. of 1,6-dr-oxo; .50 weighing 4.7 g. This is used ,without further purification A -9-ethyl0ctalin in 90 ml. absolute ethanol is added;' r for the preparation-of 1 acetoxy-6ethoxy-A -9-ethyl-trans- 200 mg. purified sodium borohydrideJA-fter -15 miriute's'," o ctalin. z; i; I t L I 200 mg. sodium borohydride is added and after a further In the above Examples '4 and 5, ethyl orthoformate is 15 minutes, 160 mg. sodium borohydride. The "stirring and nsed, other orthoformates may also be used such as meth cooling are continued for 15 minutes and thenthe solution yl,- propyl, butyl and the like. Also other strong acid cata is acidified with glacial acetic acid. The'ethanol is removed .lysts can be used in place of hydrogen chloride such as under reduced pressure and the residue partitioned besulfuric acid.

tween chloroform and water. The aqueous phase is washed When l-benzoyloxy, l-toluoyloxy or l-halobenzoyloxy, with chloroform and the combined organic phases washed 6-oxo-9-lower alkyl-A -octalin, prepared as for exwith sodium bicarbonate solution, dried and evaporated. ample, by reacting 1-hydroxy-6-oxo-9-lower alkyl-A The residue is distilled, the product, 1 hydroxy-6- oxooctalin with .benzoyl chloride or the like in pyridine, is A -9-ethyloctalin, boils at 165 C. at 0.8 The oil Substituted for l-acetoxy-6-oxo-9-lower alkyl-A -octacrystallizes and the analytical sample, melting point lin, the product from the reaction is the corresponding 1-' S8.0-89.5 C. is obtained by recrystallization from acebenzoyloxy,l-toluoyloxy or l-haloben'zoyloxy, -6-ethdxytone-hexane. w 9-lower alkyl-A t -hexahydronaphthalene. When this By employing the appropriate 1,6-dioxo'-A -9-lower starting material is employed, the products V through alkyloctalin in the above reaction, the corresponding 1-hy-' IX, illustrated on the flowsheet, have the l-acetoxy group droxy-6-oxo-A -9-lower alkyloctalin is'produced. For replaced.by-the 'l benzoyloxy, l-toluoyloxy or l-haloexample, the corresponding -9-m'ethyloctalin, -9-propyleenzey1oxy"g;oup.ij octalin, -9-butyl or isopropyloctaline may be prepared by i J 1.1 E MPLE 6 thisprocedure. l i

E SZO) n 2.5; methyl-trans-A -octalin (VI) Preparation of l'acetoxy-ti-oxo-A -9-ethyloclallr1,UV). .cm f o Ex e 4 z A mixture of 3.98 g. of 1-hydroxy-6-oxo-A -9-ethyl- 1-acetoxy-6-oxo-9-methyl-A -octalin) is dissolved in 150 ml. absolute ethanol and hydrogenated at room temperature and atmospheric pressure in the presence of 400 mg. of 2% palladium-on-strontium carbonate. One mole of hydrogen is absorbedin 2 hours. The catalyst is removed by filtration. and the ethanol evaporated under reduced pressure. The crude residue of 1-acetoxy-6-ethoxy- 9-methyl-trans-A -octalin is used directly for the preparation of 1-acetoxy-9-methyl-6-oxo-tran.s-decalin of Example 8.

In the above reaction, other hydrogenation catalysts may be used such as for example palladium on carbon, etc.

EXAMPLE 7 Preparation. of 1-acetoxy-6-ethoxy-A 9-ethyl-trans-octalin (VI) The crude enol ether of Example (4.7 g.) from 1- acetoxy-6-oxo-A -9-ethyloctalin is dissolved in 200 ml. absolute ethanol and 1.0 g. of 2% palladium hydroxide on strontium carbonate is added. The catalyst and compound .are reduced with hydrogen at atmospheric pressure. One molar equivalent of hydrogen is absorbed. The catalyst is then removed by filtration and the solvent evaporated under reduced pressure. The residue consisting predominantly of 1-acetoxy-6-ethoxy-A -9-ethyl-trans-octalin weighs 4.7 g. and is used without further purification.

Further, employing the procedure set forth in Examples 6 and 7 above and substituting an enol ether of the general formula:

OCOR' 2 Where R and R are lower alkyl, for the l-acetoxy-6- ethoxy-9-methyl A hexahydronaphthalene of Example 6 or the 1-acetoxy-6-ethoxy-9=ethyl-A -hexa hydronaphthalene of Example 7, and R' is a radical selected from the group consisting of hydrogen, lower alkyl, phenyland substituted phenyl radicals, there is produced a compound of the general formula:

H wherein R and R are lower alkyl and R is a radical as described above.

EXAMPLE 8 Preparation of 1-acetoxy-9-methyl-6-oxo-transdecalin (VII) The crude 1 acetoxy 6 ethoxy 9 methyl-trans- A -octalin is" warmed on the steam bath for 0.5 hour with 60 ml. 50% aqueous acetic acid. After cooling, the solution isdiluted with water and extracted with ether. The ether is washed twice with water followed by saturated sodium bicarbonate solution. The organic phase is dried and the solvent evaporated. The residue is crystallized from a small volume of hexane to give 4.1 grams (61%) of l acetoxy 9 methyl 6 oxo-trans-decalin, melting point 46 49 C. a

7 EXAMPLE 9 Preparation of 1-acetoxy-6-oxo-9-ethyl-transdecalin (VII) The crude l acetoxy 6 ethoxy-A -9-ethyl-trans-octalin (4.7 g.) prepared as in Example 7 is heated on a steam bath with 20 ml. water and 20 ml. glacial acetic acid for 0.5 hour. The solution is cooled, diluted with water and extracted with ether. The ether is washed with water, saturated sodium bicarbonate solution, dried and evaporated. The residue of 1-acetoxy-6-oxo-9-ethyl-transdecalin weighs 4.1 g. and is used without further purification.

Using the procedure described in Examples 8 or 9 above and reacting a compound of the formula:

OCOR' 2 where R and R are as described above.

EXAMPLE 10 Preparation of 1-acetoxy-7-bromo-6-oxo-9- methyl-trans-decalin (VIII) A mixture of 1-acetoxy-6,6-ethylened-ioxy-9-methyh trans-decalin (25 g.) and 100 ml. 50% acetic acid are heated on the steam bath for 0.5 hour. After cooling, the solution is diluted with water and extracted with ether. The ether is washed with water, saturated sodium bicarbonate, dried and evaporated. The residue of l-acetoxy- 6-oxo-9-methyl-trans-decalin weighs 20.5 g. The keto acetate is dissolved in 150 ml. chloroform and cooled to 0 C. To the stirred solution is added dropwise a solution of 15.0 g. of bromine in 75 ml. chloroform. After the addition, the chloroform-is removed under reduced pressure and'the residue crystallizes from ether to give 20.85 g. (74% overall) of the bromo ketone. The analytical sample obtained by recrystallizations of the crude prod uct from acetone-hexane has a melting point l47-1 48 C.

The compound-1 -acetoxy 7- bromo-6-oxo-9I-ethyl trans-decalin is readily prepared in good yield by'the above procedure employing l-acetoxy-d,6-ethylenedioxy 9-ethyl-trans-decalin in place of the 1-acetoxy'-6, 6-eth} /l-' enedioxy-9-methyl-trans-decalin.

EXAMPLE .11

Preparation of 1-acetoxy-6-oxo-9-methyLA' trans-octalin (IX) sample obtained byrecrystallization from ether-hexane potassium bicarbonate in ml. water are heated under reflux for 5.5 hours. The mixture is cooled, diluted with 11 water and extracted with ether. The ether is washed with water and saturated brine, dried and evaporated. The residue is crystallized from ether-hexane to give 102g. of 1 hydroxy 6 oxo 9 methyl-A' -transoctalin, melting point 86-88 C. The analytical sample has melting point 88-89 C.,

Substituting 1 acetoxy 6 x0 9 ethyI-N-transoctalin for 1 acetoxy-6-oxo-9-methyl-A -trans-octahn gives the corresponding 9-ethyl derivative (X) In good yield.

' EXAMPLE 13 Preparation of 1-t-butoxy-6-oxo-9-methyl-A trans-octalin (XI) To 25 ml. of liquid isobutylene containing 0.5 ml. of 100% phosphoric acid saturated with boron trrfluorrde is added 5.0 g. of 1 hydroxy 6 oxo-9-methyl-A -transoctalin in 25 ml. dry methylene chloride. The mixture 1s shaken overnight at room temperature. After cooling the mixture in an ice-methanolbath, excess isobutyleners removed by a stream of dry nitrogen and the resrdue is dissolved in methylene chloride. The solution washed thoroughly with saturated sodium bicarbonate solution, dried and evaporated. The residue is dissolved in hexane and passed through a plug of neutral alumina. Evaporation of the solvent yielded 5.7 g. (87%) of crystalline t-butyl ether, melting point 72-73 C.

1- The compound 1 t-butoxy-6-oxo-9-ethyl-A' -trans octalin is prepared in accordance with the above procedure employing as the starting material 1-hydroxy-6- oxo-9-ethyl-A7-trans-octalin in the place of l-hydroxy-6- oxo-9-methyl-A -trans-octalin.

EXAMPLE 14 Preparation of 1-acetoxy-6,6-ethylenedioxy-9-methy1- trans-decalin (XII) The crude 1 acetoxy 9-methyl-6-oxo-trans-decalin derived from 16 grams crude 1-acetoxy-6-ethoxy-9-methyl- A -hexahydronaphthalene by the series of reactions described in Examples 4, 6 and 8 without purification of any intermediates is heated in 250 ml. benzene containing 16 grams ethylene glycol and 200 mg. p-toluenesulphomc acid under a Dean-Stark water separator for 4 hours. The cold benzene solution is diluted with 200 ml. ether and then washed successively with saturated sodium bicar bonate solution, water and saturated brine. After drying the organic phase, the solvents are removed under reduced pressure. The residue is diluted with an equal volume of hexane and kept at 0 C. overnight. The crystalline mass is removed by filtration and washed with 20 ml. cold hexane. Total yield of 1 acetoxy-6,6-ethylenedioxy-9- methyl-trans-decalin is 9.7 grams (57% based on enol ether of Example 4), melting point 1l6-117 C. is obtained.

In the above reaction ethylene glycol is used to protect the keto group, however, other alcohols can be used such as propandiol.

' EXAMPLE 15 Preparation of l-acetoxy-6,6-ethylenedioxy-9-ethyl-transdecalin (XII) A solution of crude 1 acetoxy 6 oxo-9-ethyl-transdecalin (2.05 g.) prepared as in Example 9 dissolved in 100 ml. benzene containing 2.05 g. ethylene glycol and 100 mg. p-toluenesulphonic acid is heated under reflux under a Dean-Stark water separator until no more water is azeotropically removed (4.5 hours). The solution is cooled, diluted with ether and washed with saturated sodium bicarbonate solution. The organic phase is then washed with water followed by saturated brine, dried and the solvents removed under reduced pressure. The residue is crystallized from hexane to give 1-acetoxy-6,6-ethylenedioxy 9 ethyl-trans-decalin. The analytical sample obtained by recrystallizations of the product from acetone hexane has a melting point 78.5-79.5 C.

7 I2 A compound of the formula:

' OCOR' H as exemplified by Examples 14 and 15 above, where R is lower alkyl and R is hydrogen, lower alkyl, phenyl or substituted phenyl radical are prepared by reacting a compound of the formula:

OCOR' 2 where R and R are as described above, with benzene, ethylene glycol and an acid such as p-toluenesulphonic acid.

EXAMPLE 16 Preparation of 1-hydroxy-6,6-ethylenedioxy-9-methylv trans-decalin (XIII) A mixture of 10.72 grams (0.04 mole) of l-acetoxy- 6,6-ethylenedioxy-9-methyl-trans-decalin, ml. ethanol and 50 ml. 2 N potassium hydroxide solution are heated under refluxing conditions for 2 hours. Most of the ethanol is removed by distillation under reduced pressure, the residue is diluted with water and extracted with ether. The ether is washed with water, saturated brine, dried and evaporated. The residue crystallizes completely to give 7.9 grams (84% yield) of 1 hydroxy-6,6-ethylenedioxy-9- methyl-trans-decalin, melting point 71-72 C.

Employing the procedure of this example and substituting a l-acyloxyor 1-aroyloxy-, 6,6-ethylenedioxy-9-lower alkyl trans decalin for 1-acetoxy-6,6-ethylenedioxy-9- methyl trans-decalin will yield the corresponding l-hydroxy 6,6-ethylenedioxy-9-lower alkyl-trans-decalin. The 1 hydroxy 6,6-ethylenedioxy-9-ethyl-trans-decalin prepared by this method is a crystalline solid, melting point 9S-96 C.

EXAMPLE 17 Preparation of l-benzyloxy-6,6-ethylenedioxy-9-methyltrans-decalin (XIV, R =CH A mixture of 63 ml. benzyl chloride, 10.85 g. l-hydroxy-6,6-ethylenedioxy-9-methyl-trans-decalin (XIII, R is CH and 11.05 g. of a 54% suspension of sodium hydride in mineral oil is stirred and gradually heated. At -125 C. a vigorous exothermic reaction takes place. When the reaction has subsided, a temperature of C. is maintained for 1 hour. The mixture is diluted with benzene and filtered. The benzene and excess benzyl chloride are removed under reduced pressure and the residue distilled. The product, 1-benzyloxy-6,6-ethylenedioxy-9- methyl-trans-decalin is distilled at 176182 C. at 0.5 mm., (13.0 g.). The product (XIV, R is CH crystallizes completely and the analytical sample (from hexane) has a melting point 83 83.5 C.

When 1 hydroxy-6,6-ethylenedioxy-9-ethyl-trans-deca lin (XIII, R is C H is used in the reaction with benzyl chloride, the product is 1-benzyloxy-6,6-ethylenedioxy-9- ethyl-trans-decalin (XIV, R is C H which distills at 182-l84 C. at 0.05 mm.

EXAMPLE 18 Preparation of 1-benzyloxy-6-oxo-9-methyl-transdecalin (XV, R =CH To a solution of 130 g. of 1-benzyloxy-6,6-ethylene dioxy 9 methyl-trans-decalin (XIV, R is CH in 500 ml. glacial acetic acid is added 300 ml. water and the mixture heated on the steam bath for 0.5 hour. Approximately 200 ml. glacialacetic afeid are added and the heating continued for 1.5 hours. After-cooling the mixture, it is diluted with water and extracted with ether. The ether isxwashed with :water, saturated sodium bicarbonate solution, dried and evaporated. The residue is distilled and the ,produca hasboiling point 157 C. at 0.03 mm. The produetljcan' becrystallized from: hexane at,' 10 C. to alsolid melting point 4647 C.

j fwhen 1 i-j-"benzyloxy 6,6-ethylenedioxy-9-ethyl-trans de'calin (XIVjR is C H is hydrolyzed in the same way asdescribed"above, the product is 1-benzyloxy-6-oxo-9- ethvl trans decalin ('XV, R is C H EXAMPLE 19 Preparation of l-benzyloxy 7-bromo6-oxo-9-methyltrans-decal-in (XVI, R =CH v .A, stirred solution of 38.35 g. of 1-benzyloxy-6oxo- 9-methyl-transdecalin-in 500 ml. chloroform was cooled to C. and then 25.9 g. of bromine in 175 ml. chloroform is added dropwise at such as rate that there is never more than a small amount of free bromine present. After the addition, the solution is poured into a--saturated aqueous sodium bicarbonate solution. The two phases are well shaken, the "chloroform layer separates, is dried and evaporated. The 'residue (51.0 g.) consisting mainly'of 1 benzyloxy 7 'bromo 6-oxo-9-methyl-trans-decalin (XVI, Rg is CH is usedwithout further purification. The compound can be crystallized from acetone-hexane and theanalyticalsample melted at 112 -113 C.

When 1 f,-pberiz yloxy 6 oxo 9-ethyl transdecalin- (XV ,R C H is brominat'ed in the same way, the prodnot is If 'b'ehzyloxys 7 bromo 6 oxo-9-ethyl-transdecalin '(XVIQR 'is C H ')",'which has melting point 139- Preparationfof' l-benzyloxy 6-ox'o-9:methyl-N-transoctalin (XVII, RZFCHQ The crude l benzyloxy 7 1 bromo-6-oxo-9-methyltrans-decalin (51.0 g.) prepared as in Example 19 is dissolved in 600 ml. d ry, dimethylformamide and 35 g. of lit'liiuriica'rbon ate and 35 g. of dry lithium carbonate addedl The"'mi'xture is stirred and heated 'at reflux under nitrogen for two hours. The mixture is cooled and most of the solids removed by filtration. The filtrate is diluted with water and extracted'with ether, then ether washed with water, saturated brine,,, dried and evaporated. The residue is .fd'ist illed tb giyjel -I benzyloxy-6-oxo-9rmethyl-A' -transopt n (XV-ILL R is CH )",as a pale yellow oil, boiling.

1', y benzyloxy, 6 oxo-7-bromo-9-ethyl-transdjeca'liri '(XVLR is C H' is dehydrobrominated as described above, the, product is 1-benzyloxy-6-oxo-9-ethyl- A 'lrt'rans-olct'alin((XVII, R3 is vC H which distills at :"+,1 9igamm EXAMPLE 21.

Preparation of trans 1,2,4a,5,6,7,8,8a octahydro 4afrrieth'yl 5' T t-butoxy-Z-oxo-l-naphthaldehyde (XIX, .RFCH ,-E' -=t-buty1-) I To a stirred suspension of dry sodium methoxide (from 0.74 g; sodium) in" dry benzene under'nitrogen is added t.'5*m1;-ofr redistilled'ethyl: formate in a gentle stream. Afterstir-ringlat: room temperature for 05-hour, the mixtu re 'iscooled to 0 C. and-2.316 g.'of.1-t-butoxy-6-oxo- 9.-methyl-A '-:trans-octalin in 20 ml. dry benzene is added dropwise. The solution-is then stirred overnightat room temperaturefiWater and ether-late. added to the mixture. The'water is separated and the organic-phase extracted twice with 1N potassium hydroxide. The combined aqueous phases are acidified with-2.5 M sodium dihydrogen phosphate solutionand-thoroughly extracted with ether. lhe etl er is washed with; water, saturated brine, dried and'evaporated. The residue (2.55 g.) consisting of trans- 14 1,2,4a,5,6,7,8,8a octahydro 4a methyl-S-t-butoxy-Z- oxo-l-naphthaldehyde (XIX, R is CH R is C(CH is used without further purification.

EXAMPLE 22 Preparation of trans 1,2,4a,5,6,7,8,8a octahydro-4amethyl-S-benzyloxy-Z-oxo 1 naphthaldehyde (XIX, R =CH R=CH C H The above is prepared from 2.86 g. of crude l-benzyloxy 6 oxo 9 A' -octalin (XV, R is CH R is CH C H ethylformate (4.5 ml.), and sodium methoxide (from 0.74 g. sodium) in a manner similar to that described for the t-butoxy analog in Example 21. The transl,2,4a,5,6,7,8,8a-octahydro-4a-methyl 5 benzyloxy-Z- oxo-l-naphthaldehyde (XIX, R is CH R is CH C H (3.1 g.) is obtained as a pale yellow oil and used directly.

When the reactions described in Examples 21 and 22 use as starting materials the ethyl analog (R is C H the products are the corresponding ethyl compounds.

EXAMPLE 23 Preparation of trans 1,2,4a,5,6,7,8,8a octahydro 4amethyl 5 t butoxy-Z-oxo-1-(3-oxobutyl)-1-naphthaldehyde (XX, R =CH R'=C(CH R"'=H) The crude 1-t-butoxy-5-formyl-6-oxo-9-methyl-A' -transoctalin (2.55 g.) is dissolved in ml. dry benzene and the solvent removed to remove traces of water. This procedure is repeated. The residue is dissolved in 20 ml.

dry t-butanol and 0.87 g. freshly distilled methylvinyl ketone added. The air is displaced by nitrogen, the solution cooled down in an ice bath and 1 ml. of a 1 M solution of potassium t-butoxide in t-butanol is added. The solution is left at room temperature overnight. Ether and water are added and the aqueous phase thoroughly extracted with ether. The ether is washed with water,

saturated brine, dried and evaporated. The residue, a

viscous pale yellow oil, of trans-l,2,4a,5,6,7,8,8a-octahydro 4a methyl 5 t-butoxy-Z-oxo-l-(3-oxobutyl)-lnaphthaldehyde (XX, R is CH 'R' is C(CH R is H) is used without further purification.

EXAMPLE 24 M solution of potassium t-butoxide in t-butanol there isobtained by following the procedure as described in Ex; ample 23, trans 1,2,4a,5,6,7,8,8a-octahydro-4a-methyl 5- benzyloxy-2-oxo-1-(3-oxobuty1)-1-naphthaldehyde, is obtained as a viscous. pale yellow oil which is used without further purification.

When the procedures described in Examples 23' and 24 are carried through with the ethyl analog, the products obtained are the 4a-ethyl naphthaldehydes;

EXAMPLE 25 Preparation of trans 1,2,4a,5,6,7,8,8a octahydro 4amethyl-S -benzyloxy-2-oxo- 1- 3 oxopentyl)-1'-naphthal- The above compound is prepared from trans-I,2,4a,5,6, 7,8,8a-octahydro-4a-methyl 5 benzyloxy- 2-oxo-1-naphthaldehyde (XIX, R is CH R is on c m and ethyl-' vinyl ketone by the procedure described in Example 24.

EXAMPLE 26 Preparation of methyl trans-l-formyl- 1,2,4a,5,6,7,'8,8aoctahydro-4a-methyl 5 t butoxy-6,2-dioxo-1-naphthaleneheptanoate (XX, R=CH R'=C(CH R"=CH CH COOCH The crude trans-1,2,4a,5,6,7,8,8a-octahydro-4a-methyl- S-t-butoxy-Z-oxo-l-naphthaldehyde prepared in Example 21 is dissolved in 5 ml. dry t-butanol and 1.87 g. methyl 5-oxo-6-heptenoate added. After cooling the solution under a nitrogen atmosphere, 1 ml. of a 1 molar solution of potassium t-butoxide in t-butanol is added and the mixture kept at room temperature overnight. The solution is diluted with water and ether and the aqueous phase thoroughly extracted with ether. The ether is washed with water, and saturated brine, dried and evaporated. The residue of methyl trans-l-formyl-1,2,4a,5,6,7,8,8a-octahydro-4a-methyl-5-t-butoxy 6,2 dioxo 1 naphthaleneheptanoate (XX, R is CH R is C(CH R" is CH CH COOCH is obtained as a viscous, pale yellow oil, and is used without further purification. The methyl acetate analog i.e. where R" is CH COOCH can also be prepared by this procedure using methyl 4-oxo-5-hexenoate instead of 5-oxo-6-heptenoate.

EXAMPLE 27 Preparation of methyl trans-l-formyl-1,2,4a,5,6,7,8,8aoctahydro 4a methyl-5-benzyloxy-5,2-dioxo-l-naphthaleneheptanoate (XX, R =CH R' =CH C H This is prepared from the crude trans-l,2,4a,5,6,7,8,8aoctahydro-4a-methyl 5 benzyloxy-Z-oxo-l-naphthaldehyde, 3.1 g., described in Example 22, 1.87 g. of methyl 5- oxo-6-heptenoate and 1 ml. of a l M solution of potassium t-butoxide in t-butanol by the procedure described in Example 26.

The product, methyl trans-l-formyl-l,2,4a,5,6,7,8,8aoctahydro 4a methyl 5 benzyloxy-6,2-dioxol-naphthaleneheptanoate (XX, R is CH R is CH C H R is CH CH COOCH is obtained as a pale yellow viscous oil and was used in this form without further purification. The methyl acetate analog of the above compound, i.e. where R" is CH COOCHg, can be prepared by this procedure with methyl 4-oxo-5-hexenoate in place of methyl 5-oxo-6-heptenoate.

EXAMPLE 28 The crude trans-1,2,4a,5,6,7,8,8a-octahydro-4a-methyl- 5-t-butoxy-2-oxo-l-(3 oxobutyl)-l-naphthaldehyde prepared in Example 23 is dissolved in 25 ml. dioxane and cooled to C. A solution of 1.7 g. potassium hydroxide in 25 ml. water is added and the air displaced by nitrogen. After standing at room temperature for 3 hours, ether and water are added to the mixture and the aqueous phase thoroughly extracted with ether. The ether is washed with water and saturated brine, dried and evaporated. The residue is crystallized from ether-hexane. The analytical sample crystallized from hexane has the melting point 134-135 C.

EXAMPLE 29 The above is prepared from trans-1,2,4a,5,6,7,8,8a-octahydr0-4a-methyl benzyloxy-2-oxo-1-(3-oxobutyl)-lnaphthalaldehyde (prepared as in Example 24) in 25 ml. dioxane and 1.7 g. potassium hydroxide in 25 ml. water as described in Example 28. The crude product is chromatographed on alumina to yield dl-8/3-benzyloxy- 8afi-methyl-4,4a,8,4ba,5,6,7,8,8a octahydro-2(3I-I)-phen anthrone. An analytical sample, recrystallized from methanol, has melting point l09-110 C.

1 EXAMPLE 30 7 This is prepared from trans-1,2,4a,5,6,7,8,8a-octahy dro-4a-methyl-S-benzyloxy-2-oxo-1 (3 oxopentyl)-lnaphthaldehyde (XX, R is CH R is CH C H by the procedure described in Example 28 to give the product dl-8/8-benzyloxy-8afi,l dimethyl 4 4afl,4ba,5,6,7,8,8a octahydro -2(3H) -phenanthrone (XXI, wherein R is CH3, R, IS CH C H and R," IS CH3).

EXAMPLE 31 Preparation of dl-2,3,4,'4ap,'4bu,5,6,7,8,8a decahydro- SaB-methyl-8fl-t-butoxy-2-oxophenanthrene 1 -propionic acid (XXI, R =CH R'=C(CH Crude methyl trans-l-formyl-l,2,4a,5,6,7,8,8a -octahydro-4a-methyl-5-t-butoxy-6,2 dioxo 1 naphthaleneheptanoate (3.0 g.) prepared in Example 26 is dissolved in 15 ml. dioxane and 30 ml. of a 1.6 Msolution of sodium hydroxide added. The mixture is stirred overnight at room temperature under nitrogen. The solutionis diluted with water and extracted with ether. The aqueous phase is acidified with 6 N sulphuric acid and rapidly extracted with ether. The ether is washed twice with water followed by saturated brine solution. The ether is dried and evaporated. The residue (2.0 g.) is exhaustively extracted with boiling cyclohexane. The cyclohexane is evaporated and the residue crystallized from acetonitrile. The analytical sample recrystallized from the same solvent has melting point 88-89 C. The acetic acid analog of this compound, where R' is CH COOH, may be prepared employing the methyl acetate analog of compound (XX) in the reaction.

EXAMPLE 32 Preparation of dl-2,3,4,4a}9, 4ba, 5,6,7,8,8a-decahydro- 8afi-methyl-85-henzyloxy-2-oxo-phenanthrene-1 propi- OIliC acid R2=CH3, RI==CH2C6H5, Y

Preparation of dl-8B-t-butoxy-8afl-methyl-4,4ap,'4ba,5,6,

7,8,8a,9,l0-decahydro 2(3H) phenanthrene, (XXII 'Whrein R2 is CH3, R is C(CH3)3, R, is

A suspension of 25 mg. of 2% palladium hydroxide on strontium carbonate in 5 ml. dry benzene is reduced with hydrogen at atmospheric pressure. When the "reduction is complete 54.4 mg. of dl-8 3-t-butoxy-8a;3-methyladded and the reduction continued. After 7 minutes,

4.54 ml. of hydrogen has been absorbed and there is no further absorption. The catalyst is removed by filtration and the solvent removed under reduced pressure. The

residue crystallized and the solid is recrystallized from hexane at 10 C. to give d1-8/8-t-butoxy-8aB-methyl-4,

4afi,4ba,5,6,7,8,8a,9,l0-decahydro-2(3H) phenanthrene, melting point 97 -98 C.

1 7 EXAMPLE 34 Preparation of dl-SB-benzyloxy-Safl-methyl 4,4a,B,4bu,5, 6,7,8,8a,9,10-decahydro-2(3H) phenanthrone (XXII, wherein R is CH R is CH C H and R' is H) Reduction of 43.7 mg. of d1-8/8-benzyloxy-8a/8-methyl- 4,4afl,4ba,5,6,7,8,8a-octahydro 2(3H) phenanthrone in benzene with 25 mg. of 2% palladium hydroxide on strontium carbonate as described in Example 33 gives dl-8;8-benzyloxy-8aB methyl 4,4aB,4bu,5,6,7,8,8a,9,10- decahydro 2(3H) phenanthrone, melting point 101- 102 C.

EXAMPLE 35 Preparation of d1-8B-benzyloxy 2,3,4,4a;3,4ba,5,6,7,8,8a,

9,10-dodecahydro-SaB-methyl 2 oxo-phenanthrenel-propionic acid (XXI wherein R is CH R is CH C H and R' is CH CH COOH) A suspension of 1.0 g. of 2% palladium hydroxide on strontium carbonate is reduced in 30 ml. water with hydrogen at atmospheric pressure and room temperature. A solution of 3.94 g. of dI-SB-benzyloxy-Z,3,4,4afi,4ba, 5,6,7,8,8a-decahydro-8afl-methyl-2-oxo-phenanthrene 1- propion-ic acid in 10 ml. of 1 'N sodium hydroxide is added. When 1 molar equivalent of hydrogen has been absorbed, the catalyst is removed by filtration and the aqueous phase acidified with dilute hydrochloric acid. The aqueous phase is thoroughly extracted with ether, the ether washed with water, saturated brine, dried and evaporated. The residue (4.0 g.) of crude dl-8B-benzyloxy- 2,3,4,4afl,4ba,5,6,7,8,8a,9,l-dodecahydro 8aB methyl- 2-oxo-phenanthrene-l-propionic acid is used without further purification.

The procedures detailed in Examples 25 through 35 for the methyl compounds R =CH in generic formulas are equally useful when R is C H and yield the corresponding product. This also applies where R" is methyl acetate (XX) and following reactions yield XXI and XXII where R' is CH COOH.

EXAMPLE 36 Preparation of dl-17a 3-benzyloxy-5-hydroxy-3,5-seco- 4- nor(),9l( 1 1 )-D-homoestradien-3-oic acid, 4,5 -lactone (XXIII wherein R is CH and R is OH CgI-I l A solution of 4 .g. of dl-8/3-benzyloxy-2,3,4,4ap,4ba, 5,6,7,8,8a,9,l0-dodecahydro-8ap-methyl-2 oxo phenanthrene-l-propionic acid in 40 ml. acetic anhydride and 50 mg. anhydrous sodium acetate is heated under reflux under nitrogen for 4 hours. The solvents are evaporated under reduced pressure and the residue dissolved in ether and water. The aqueous phase is thoroughly extracted with ether, the ether phase combined and washed successively with l M sodium carbonate solution, water and saturated brine. The ether is separated, dried and evaporated. The residue is crystallized from ether to give d1- 17afi-benzyloxy-5-hydroxy-3,5-seco-4-nor 5 10) ,9 1 l D-homoestradien-3-oic acid, 3,5-lactone, melting point 13013l C.

EXAMPLE 37 Preparation of dl-17ap-benzyloxy-5-hydroxy-3,5-seco-4- nor 5(10) D homoestren 3 oic acid, 3,5-lactone (XXIV, wherein R is CH and R is CH C H A suspension of 0.5 g. of 2% palladium hydroxide on strontium carbonate in 40 ml. dry benzene is reduced with hydrogen at room temperature and atmospheric pressure. Then 1.76 g. of dl-l7a,!3-benzyloxy-5-hydroxy- 3,5 seco 4 nor 5(10),9(1l) D homoestradien-3- oic acid, 3,5-lactone in 40 ml. dry benzene is added and the reduction continued. During 22 hours, ml. of hydrogen had been absorbed and the catalyst is then removed by filtration and the solvent evaporated. The residue is dissolved in ether and percolated through a plug of Florisil. The Plorisil is washed with more ether and the combined ether solutions evaporated and the residue crystallized from an ether-hexane mixture to give dl 17a,8 benzyloxy 5 hydroxy 3,5 seco 4 nor- 5(10)-D-homoestren-3-oic acid, 3,5-lact0ne, melting point l23-124 C.

EXAMPLE 38 Preparation of dl-19-nor D-homotestosterone, benzyl ether (XXV wherein R is CH, and R is CH C H A solution of 0.5 g. dl-l7afl-benzyloxy-5-hydroxy-3,5- seco-4-nor-5(10)-tD-homoestren-3-oic acid, 3,5-lact0ne in 100 ml. ether and 30 ml. benzene is cooled to 50 C. under nitrogen and 2 ml. of a 3 M solution of methyl magnesium bromide in ether is added with stirring over 20 minutes. After stirring a further :1 hour at 50 C., 2 N hydrochloric acid is added and the mixture warmed to room temperature. The organic phase is diluted with benzene and the aqueous phase thoroughly extracted. The organic phase is washed wtih a 1 M sodium carbonate solution, water, dried and evaporated to give 0.55 g. of a colorless oil. The oil is dissolved in 15 ml. glacial acetic acid and 1.5 ml. concentrated hydrochloric acid is added. The solution is allowed to stand under nitrogen at room temperature for 48 hours. The solvents are removed under reduced pressure and the residue dissolved in benzene. The benzene is washed with saturated sodium bicarbonate, water, saturated brine, dried and evaporated to give a crystalline residue. This is recrystallized from ethanol to give 300 mg. 19-nor-D-homotestosterone, benzyl ether, melting point -l8 8 C. A pure sample is prepared by recrystallization from a chloroform-ethanol mixture. The analytical sample has melting point 194- 195 C.

The procedures outlined in Examples 36, 37 and 38 are equally applicable when R in the generic formula is ethyl. In this instance the products are the corresponding ethyl compounds.

I claim:

1. A compound of the formula:

0-0 CH Re ale UNITED STATES PATENTS 2,802,873 '8/1957 Woodward 260-586 H BERNARD HELFIN, Primary Examiner N. MORGAN'STERN, Assistant Examinen US. Cl. X.R.

260-340.'9, 343.2 S, 343.3, 468 R, 469, 488 B, 586 H, 483, 590; 42=4242 

